Progressive loss of cognitive skills, a hallmark of neurodegenerative diseases such as Alzheimer's (AD), represents a major challenge to healthcare implementation. No satisfactory treatments for AD currently exist, and multiple approaches will be necessary for successful therapeutic management. Among these approaches is effective pharmacologic intervention to ameliorate cognitive deficits associated with AD and other neurodegenerative diseases. Ubiquitin E3 ligases are a class of molecular target recently linked to a variety of pathologies, including synaptic function and regulation of te response to oxidative stress in neurons and other cell types. IDOL is one such ligase; it is known to ubiquitylate and promote the degradation of certain receptors, including ApoER2 and VLDLR, which are the major receptors for the glycoprotein Reelin in the brain. Reelin is a principal regulator of memory/cognition; via signal transduction mediated by ApoER2 and VLDLR, Reelin binding increases long term potentiation and synaptic plasticity. Numerous knock-out and knock-in studies as well as murine models show that Reelin exerts a positive effect on learning and memory; thus, augmentation of Reelin signaling is very likely to offer benefit in treating cognitive decline in AD and related diseases. Because IDOL is responsible for down-regulating Reelin, the therapeutic hypothesis addressed in the proposed project is that IDOL is a tractable novel target for developing small molecule inhibitors that will augment Reelin signaling. Inhibitors of IDOL are expected to increase ApoER2 and VLDLR levels in the brain and enhance Reelin mediated synaptic plasticity. Using a thermal shift based pilot screen, Progenra has discovered several IDOL inhibitors, and preliminary data demonstrate that one of these IDOL inhibitors, P0085255, stabilizes ApoER2. In the proposed project, novel small molecules that enhance or stimulate Reelin signaling in the brain by interfering with IDOL and stabilizing ApoER2 and VLDLR will be discovered and advanced toward pre-clinical development. Inhibitors already in hand will be developed by chemical optimization, and additional inhibitors will be identified by further screening of Progenra's entire small molecule library and optimized similarly. Selected inhibitors will be evaluated using a combination of biochemical, cellular, and in vivo model systems for their ability to stabilize ApoER2 and VLDLR as well as to modulate Reelin signaling biomarkers. In Phase II, the most promising compounds will advance into preclinical development using appropriate animal models for memory and cognition.